Human Genetics

, Volume 138, Issue 1, pp 83–92 | Cite as

Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype–phenotype correlations

  • Qiqi Wang
  • Da Li
  • Baozhu Cai
  • Qing Chen
  • Caihua Li
  • Yanhua Wu
  • Li Jin
  • Xiuxia Wang
  • Xiaojin ZhangEmail author
  • Feng ZhangEmail author
Original Investigation


Premature ovarian insufficiency (POI) is a severe female disorder characterized by primary or secondary amenorrhea before 40 years of age. Genetic factors have been implicated in the pathogenesis of POI, but known POI-associated genes account for only a small fraction of heritability. Here, we performed whole-exome sequencing (WES) to explore pathogenic genes in Han Chinese subjects with POI. Intriguingly, we identified novel or rare heterozygous missense variants of SALL4 (spalt-like transcription factor 4) in 3 (6%) of 50 POI subjects. The SALL4 c.541G>A and c.2279C>T variants were paternally inherited, while c.1790A>G was inherited from an affected mother with early menopause. SALL4 encodes a transcription factor that is highly expressed in oocytes and early embryos. Our in vitro functional assays suggested that all of these SALL4 missense variants had significantly increased SALL4 protein expression with enhanced regulatory activity in regard to its downstream target POU5F1 compared to that of wild-type SALL4. Notably, previous studies demonstrated the genetic involvement of SALL4 loss-of-function variants in Okihiro syndrome and related syndromic developmental disorders. Through our analysis of genotype–phenotype correlations, we suggest that different variation types of SALL4 might have different effects on SALL4 activity, resulting in phenotypic variability. Our findings highlight the genetic contribution of SALL4 missense variants with enhanced regulatory activities to POI and underscore the importance of variant classification and evaluation for molecular diagnosis and genetic counseling.



We are grateful to the subjects and their families who participated in this study. We also thank Shuxia Chen for experimental support. This work was supported by National Key Research and Development Program of China (2017YFC1001100), National Natural Science Foundation of China (31625015 and 31521003), Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life SciencesFudan UniversityShanghaiChina
  2. 2.Center for Global Health, School of Public HealthNanjing Medical UniversityNanjingChina
  3. 3.Shanghai Key Laboratory of Female Reproductive Endocrine Related DiseasesShanghaiChina
  4. 4.Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangChina
  5. 5.Genesky Biotechnologies Inc.ShanghaiChina

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